Although energy homeostasis is central in feeding behavior, the decision to eat is not merely a question of hunger. In a natural environment in which food is often scarce, evaluating the benefit of gaining food over the energy cost or risk in seeking and acquiring food, and the decision to either seek food or stay put and conserve energy is essential for survival. However, the genetic and molecular basis of food-seeking decision-making behaviors, and their functional significance in fitness are poorly understood. We propose a bottom-up approach: starting from well-defined behaviors that are essential for food-seeking decision-making in Drosophila, taking advantage of its rich genetic tools and genomic resources. Moreover, flies are ideal for viability studies to examine the relations between genetic variations, differences in decision- making and differences in fitness under different environmental conditions. We have already taken the critical step and designed novel assays. We will optimize the following assays for quantitative analysis in this application. Decision-making in choosing between 1) small free reward or large reward that requires work; 2) small reward or large reward with a relatively low probability in its availability; 3) small reward or large reward that is paired with potential risks of getting noxious food; and 4) immediate small reward or delayed large reward. We will take advantage of natural variation in genetics and behaviors between different D. melanogaster populations living in African. We will establish 200 recombinant inbred strains derived from original African strains with extreme behavioral phenotypes for each decision-making behavior. We will perform QTL mapping and identify QTLs that contribute to the variations in food-seeking decision-making and fitness. We will then use RNAi transgenic lines to identify specific genes and variants responsible for the above behavioral variations. Although the most likely immediate clinical relevance of our study is obesity, it will have a much broader impact on neuroeconomics, the genetic basis of behavior in general, evolution and ecology. PUBLIC HEALTH RELEVANCE: We propose to establish a reliable and efficient model system that can be used to systematically search for genes and molecular pathways involved in feeding behavior, obesity and their therapeutic targets.